The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art to the present invention.
Diseases of the prostate may be divided into three major conditions. (a) Prostatitis is an inflammation of the prostate. There are four different forms of prostatitis, each with different causes and treatments. Categories 1 (acute prostatitis) and 11 (chronic bacterial prostatitis) are uncommon, and are treated with antibiotics. Category IV is a type of leukocytosis. Category III prostatitis comprises about 95% of diagnoses, and is a chronic non-bacterial prostatitis, also known as male chronic pelvic pain syndrome. (b) Benign prostatic hyperplasia (BPH), a benign enlargement of the prostate that occurs in older men, causing urinary obstruction, increased urinary frequency, pain and discomfort. Urinary frequency due to bladder spasm, common in older men, may be confused with prostatic hyperplasia. (c) Prostate cancer is the most common cancer diagnosed in men today, with a lifetime risk of diagnosis of approximately 16%. Wright and Lange “Newer potential biomarkers in prostate cancer” Reviews in Urology 9(4): 207-213 (2007).
Similar diseases may also be seen in Skene's gland (also known as “female prostate” “prostate-like” or simply “prostate”), a smaller, female equivalent to the male prostate gland that also expresses PSA. This gland may also become diseased, including cancerous, resulting in elevated PSA levels.
Early detection and diagnosis of prostate cancer currently relies on digital rectal examination (DRE), prostate specific antigen (PSA) measurements, transrectal ultrasonography (TRUS), and transrectal needle biopsy (TRNB). U.S. Patent Application Publication No. 2009/0226921. Serum PSA measurements in combination with DRE represent the leading diagnostic approach at present. (Wright and Lange, Id.) PSA is prostate specific, but not prostate-cancer specific, and PSA levels are also elevated in prostatitis and BPH. The positive predictive value for cancer of a PSA>4.0 ng/mL is only 25% from a pooled metaanalysis. Lower cut-offs (e.g. 2.5 ng/mL) increase detection but decreases specificity, leading to unnecessary biopsies. Id.
A number of biomarkers have been proposed or are under investigation for detection of prostate cancer. These include PSA isoforms, human kallikreins, CpG methylation of GSTP1 and other loci (including APC, RASSF1a, RARβ2), PCA3 RNA, alpha methylacyl CoA racemase mRNA, autoantibodies, and genetic translocations. One of the most commonly tested translocations involves the ETS-related genes (ERG) at 21q22.2 and ETV1 at 7p21.2 with TMPRSS2 (21 q22.3). The fusion of these genes is seen in 40%-80% of prostate cancer patients, approximately 20% of prostatic intraepithelial neoplasia (PIN) cases, and rarely in benign prostatic tissue. Id.
TMPRSS2 is androgen regulated gene encoding “transmembrane protease, serine 2,” but its function is unknown. Id. TMPRSS2 is expressed both in prostate cancer, and in normal prostate tissue. Lin et al. “Prostate-localized and Androgen-regulated Expression of the Membrane-bound Serine Protease TMPRSS2” Cancer Research 59, 4180-4184 (1999).